Composition for removing abnormal keratinous material

ABSTRACT

The present invention discloses a pharmaceutical preparation comprising urea, a hydrophilic film-forming agent, water and/or a water-alcohol mixture that is suitable for the removal of abnormal keratinous material.

[0001] The present invention relates to a preparation comprising urea, ahydrophilic film-forming agent and water or an alcohol/water mixture.The preparation is useful in the removal of abnormal keratinousmaterial, as is to be observed, for example, in onychomycoses, psoriasisof the nail, or warts. With respect to the abnormal keratinous material,histological hyperparakeratosis is discernibleas an abnormally changedlayer structure of the skin or of the nail and may be treated with thepresently disclosed preparation. Moreover, by means of this inventionbrittle nails can be rehydrated, thus regenerating, for example, thephysiological barrier function of the nails.

[0002] Urea has been used in dermatological practice for decades in theform of creams and lotions. Urea changes the structure and theproperties of the keratin in the horny layer of the nails. It generallyhas a hygroscopic action in the horny layer (depending on the carrier),and an antiproliferative action on the epidermis. Urea cleaves disulfidebonds and hydrogen bonds. Through this action, the dead keratinizedmaterial is loosened and can then be mechanically detached.

[0003] For the detachment or dissolution of changed nails, in particularthose that are fungally infested, a cream containing 20% urea(Onychomal®), and an ointment containing 40% urea and the antimycoticBifonazol® (1%), along have been marketed in a joint pack together withwaterproof plasters, an aid for squeezing out, and a nail scraper(Mycospor® nail set). These preparations have been commerciallyavailable for over 10 years (Bang DS, Lee YD, Whang KK, Lee SN,“Therapeutic trial of ointment base including urea and antifungal agentas the treatment of onychomycosis,” Ann. Dermatol., 3: 32-6 (1991); HayRJ, Roberts DT, Doherty VR, Richardson MD, Midgley G, “The topicaltreatment of onychomycosis using a new combined urea/imidazolepreparation,” Clin. Exper. Dermatol., 13: 164-167, (1988)).

[0004] In addition, a nail varnish comprising a hydrophobic film-formingagent, an antimycotic, and urea, which is employed for the treatment ofonychomycoses has been described (U.S. Pat. No. 5,346,692).

[0005] Disadvantages in the use of these known preparations includefrequent maceration and inflammatory changes in the surrounding skin.Moreover, these semisolid preparations necessitate a dressing on theaffected sites in order to prevent wiping off and protection of thesurrounding tissue, e.g., by covering with zinc paste. Decisive successwas denied to the known treatment methods, since such treatments—forexample those requiring plasters on the toes and fingers that arebothersome and appear unsightly and must be applied daily —arefrequently not completed by the patients for cosmetic reasons and forreasons of time. The time needed for these customary processes iscomparatively high, and the acceptance is limited or the compliance israpidly exhausted, if, for example, more than 3 to 5 nails have to betreated.

[0006] For the detachment of indurated areas of skin such as in the caseof warts, salicylic acid preparations are customarily used in the formof semisolid preparations such as salicyl petroleum jelly (approximately20%-60%) or plasters (Guttaplast®). Here too, the disadvantages of thesemisolid preparations apply analogously.

[0007] The invention provides a preparation comprising a hydrophilicfilm-forming agent, urea, water and/or an alcohol/water mixture, whichovercomes the disadvantages mentioned for the prior art compounds.

[0008] The preparation according to the invention is an aqueous oraqueous-alcoholic solution, in which the hydrophilic film-forming agentand urea are dissolved or optionally suspended. A solution isadvantageous. After application to the abnormal keratinous material suchas warts or fingernails, the preparation rapidly forms an adherent filmwhich is resistant to wiping and rubbing off. The urea penetrates intothe abnormal keratin and assists its detachment. Additional coveringwith plasters, application of a special protective film for the areas ofskin surrounding the target site, and daily bathing are not necessary.The preparation according to the invention also prevents undesirableprecipitation reactions of the urea that occur locally on the keratinousmaterial being treated. Such precipitation leads to unsightly changes orto possible impairment of the local bioavailability of the urea. Thepreparation according to the invention makes possible a uniformdistribution of the urea on the keratinous material as a result of itscomposition and its pharmaceutical properties.

[0009] Unlike the products known in the prior art, the inventiontherefore offers several advantages. For instance, the present inventionprovides markedly improved drug targeting by permitting focusedapplication to the target organ or target site with decreased risk forexposure to the adjacent tissue, and an improved user-friendliness(handling) in the application of the preparation.

[0010] The preparation according to the invention therefore provides aformulation comprising

[0011] a) one or more nonvolatile constituents,

[0012] b) urea in an amount from 40 to 70 percent by weight, relative tothe non-volatile constituents of the preparations,

[0013] c) a hydrophilic film-forming agent and

[0014] d) water or an alcohol-water mixture.

[0015] The preparation can contain further volatile and nonvolatileconstituents as long as the amount of urea, based on the nonvolatileconstituents of the preparations, is within the specified range.

[0016] The amounts of urea are in each case based on the nonvolatileconstituents of the preparation according to the invention and can befrom 41 percent by weight to 69 percent by weight, from 45 percent byweight to 65 percent by weight, from 46 percent by weight to 63 percentby weight, or from 55 percent by weight to 63 percent by weight.

[0017] Possible hydrophilic film-forming agents include, for example,acrylic/methacrylic acid ester copolymers, polyvinylpyrrolidones,polyvinyl alcohols, vinyl acetate/vinylpyrrolidone copolymers, vinylacetate/crotonic acid copolymers, methyl vinyl ether/maleic acidcopolymers, polyesters, polyester amides, carboxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, and a mixture of two or more of thefilm-forming agents mentioned. In one embodiment, the hydrophilicfilm-forming agent is a polyvinylpyrrolidone.

[0018] The hydrophilic film-forming agents are employed in amounts from30 percent by weight to 60 percent by weight, relative to thenonvolatile constituents of the preparation. The amount of thehydrophilic film-forming agents needed will typically depend on theamount of urea in the preparation.

[0019] In the aqueous-alcoholic solutions, suitable alcohols include,for example, (C₁-C₆)-alcohols such as methanol, ethanol, propanol,isopropanol (2-propanol), butanol, pentanol hexanol or mixtures thereof.In one embodiment, ethanol, n-propanol or 2-propanol are employed. Inthe aqueous-alcoholic solutions, the ratio of alcohol to water typicallyranges from 9:1 to 1:9; In one embodiment, the mixture comprises 2 partsof alcohols to 3 parts of water.

[0020] Suitable additional excipients include plasticizers, such asglycerol triacetate or 1,2-propylene glycol, and agents for adjustingthe pH of the preparations, such as lactic acid or citric acid. In oneembodiment, the preparation comprises lactic acid in an amount from 0.5percent by weight to 5 percent by weight, based on the weight of theentire preparation.

[0021] The preparations according to the invention can furthermorecontain additives that are customary in cosmetics, such as plasticizersbased on phthalate, glyceryl triacetate or camphor, colorants or colorpigments, pearl luster agents, sulfonamide resins,sedimentation-delaying agents, silicates, odoriferous substances,wetting agents such as sodium dioctylsulfosuccinate, lanolinderivatives, sunscreen agents such as 2-hydroxy-4-methoxybenzophenone orantibacterially active substances. Colored or pigmented nail varnishes,for example, have the advantage that the preparation according to theinvention can be tailored to the perception of beauty of the patient andthe nail changes existing in the meantime are not immediately visible tothird parties.

[0022] The preparation according to the invention is typically preparedby introducing urea and a hydrophilic film-forming agent into water or awater/alcohol mixture and subsequently mixing. In one embodiment,aqueous-alcoholic solutions are prepared in which the urea is present indissolved form in an amount from 15 percent by weight to 35 percent byweight, based on the weight of the entire solution. The amount ofhydrophilic film-forming agent employed is from approximately 15 percentby weight to approximately 35 percent by weight, in each case based onthe weight of the entire solution. The amount of the hydrophilicfilm-forming agent employed generally depends on the amount of ureapresent in the preparation. The amount of water or aqueous-alcoholicmixture is from 30 percent by weight to 60 percent by weight, or from 35percent by weight to 55 percent by weight, in each case based on theweight of the entire solution.

[0023] The preparation according to the invention is typicially appliedas a solution to the keratinous materials to be treated. It driesrapidly, forming an adherent film which is resistant to wiping andrubbing off. The solution can be applied, for example, with a brush.

[0024] The invention further relates to use of the preparation accordingto the invention for the detachment of abnormal keratinous material.

[0025] The term “abnormal keratinous material ” is understood as meaningkeratinous material in humans and animals such as warts, calluses, hardskin, or toenails and fingernails that have been changed by fungalattack or psoriatic disease. With respect to the abnormal keratinousmaterial, histological hyperparakeratosis is discernibleas an abnormallymodified layer structure of the skin or the nail.

[0026] The invention also relates to the use of a preparation comprising

[0027] a) one or more nonvolatile constituents

[0028] b) urea in an amount from 30 percent by weight to 90 percent byweight, relative to the nonvolatile constituents of the preparation,

[0029] c) a hydrophilic film-forming agent and

[0030] d) water or an alcohol-water mixture

[0031] for the production of a pharmaceutical for the treatment anddetachment of abnormal keratinous material.

[0032] The amounts of urea are in each case based on the nonvolatileconstituents of the use according to the invention and can be from 35 to85 percent by weight, from 39 percent by weight to 83 percent by weight,from 46 percent by weight to 63 percent by weight, or from 55 percent byweight to 63 percent by weight.

[0033] The hydrophilic film-forming agents are typically employed inamounts from 10 percent by weight to 70 percent by weight, based on thenonvolatile constituents. The amount of the hydrophilic film-formingagents employed depends on the amount of urea. For example, mixtures ofapproximately 25 percent by weight to 35 percent by weight of urea with15 percent by weight to 20 percent by weight of hydrophilic film-formingagent may be employed, where the weight percentages are relative to thenonvolatile constituents. Such preparations will generally have ashorter drying time than formulations having a higher or lower contentof hydrophilic film-forming agent.

[0034] In the uses according to the invention, suitable alcohols,film-forming agents, and additional excipients and nonvolatileconstituents are as described above for the the pharmaceuticalpreparation The amounts of water and/or alcohol, film-forming agents,and additional excipients and non-volatile constituents are also asdescribed above.

[0035] The invention also relates to the use of an aqueous solutioncomprising urea in an amount from 15 percent to 35 percent, or from 25percent to 33 percent, based on the weight of the entire solution; and ahydrophilic film-forming agent in an amount from approximately 15percent to approximately 35 percent, or from 17 percent to 25 percent,in each case based on the weight of the entire solution, for theproduction of a pharmaceutical for the treatment of abnormal keratinousmaterial.

[0036] The abnormal keratinous material is detached by applying thepreparation, allowing a suitable amount of time for the action of thedried preparation on the keratinous material being treated, andsubsequent mechanical removal of the abnormal keratinous material.

[0037] The invention further relates to the use of the preparationaccording to the invention for the hydration of brittle toenails orfingernails.

[0038] The present invention is explained in greater detail by means ofthe following examples, but not restricted to these. If not notedotherwise, the quantitative data are based on the weight.

EXAMPLES

[0039] Example 1

[0040] A preparation according to the invention has the followingcomposition: Urea 30% Polyvinylpyrrolidone (molecular weightapproximately 11 500) 20% Demineralized water 50%

[0041] Example 2

[0042] A preparation according to the invention has the followingcomposition: Urea 30% Polyvinylpyrrolidone (molecular weightapproximately 11 500) 20% Ethanol 20% Demineralized water 30%

[0043] Example 3

[0044] A preparation according to the invention has the followingcomposition: Urea 30% Polyvinylpyrrolidone (molecular weightapproximately 11 500) 20% Propan-2-ol 20% Lactic acid  1% Demineralizedwater 29%

[0045] Example 4

[0046] A preparation according to the invention has the followingcomposition: Urea 30% Polyvinylpyrrolidone (molecular weightapproximately 11 500) 20% Lactic acid  1%

[0047] Example 5

[0048] A preparation according to the invention has the followingcomposition: Urea 30% Polyvinylpyrrolidone (molecular weightapproximately 15 000) 20% Propan-2-ol 20% Demineralized water 30%

[0049] Example 6

[0050] A preparation according to the invention has the followingcomposition: Urea 30% Polyvinylpyrrolidone (molecular weightapproximately 11 500) 20% Cremophor EL  1% Lactic acid  1%

[0051] Example 7

[0052] Activity Testing

[0053] The toenails of two affected patients were treated with thepreparation as in Example 3. The preparation of Example 3 was appliedonce daily to the affected nails with a brush before going to bed. Theurea-containing film which formed after the application to the nails waswipe-resistant and waterproof. Special protection of the skin areassurrounding the nails and the application of plaster dressings weretherefore not necessary. Because of the high water content of thepreparations, the affected toenails were not additionally bathed.

[0054] After treatment for approximately 6 days, one of the patientsremoved the affected areas of the nail and the subungual tissue debriseasily with a scraper. The severe nail brittleness had disappeared andthe severe hyperkeratosis had improved to a medium degree of severity.After treatment for approximately 6 weeks, the second patient showedthat his severe nail brittleness had disappeared and the severehyperkeratosis was no longer present.

[0055] Both patients showed a good treatment result. The tolerability ofthe preparation according to the invention was very good. Both patientswere very satisfied with the handleability in the application of thepreparation.

We claim:
 1. A pharmaceutical preparation comprising a) one or morenonvolatile contituents b) urea in an amount from 40 percent by weightto 70 percent by weight, relative to the nonvolatile constituents of thepreparation, c) a hydrophilic film-forming agent, and d) water or analcohol-water mixture.
 2. The preparation of claim 1, wherein urea ispresent in an amount from 41 percent by weight to 69 percent by weight,relative to the nonvolatile contituents of the preparation.
 3. Thepreparation of claim 1, wherein the hydrophilic film-forming agent ispresent in an amount from 29 percent by weight to 59 percent by weight,relative to the nonvolatile constituents of the preparation.
 4. Thepreparation of claim 1, wherein urea is present in an amount from 45percent by weight to 65 percent by weight, relative to the nonvolatileconstituents of the preparation.
 5. The preparation of claim 1, whereinurea is present in an amount from 46 percent by weight to 63 percent byweight, realtive to the nonvolatile constituents of the preparation. 6.The preparation of claim 1, wherein urea is present in an amount from 55percent by weight to 63 percent by weight, relative to the nonvolatileconstituents of the preparation.
 7. The preparation of claim 1, whereinthe hydrophilic film-forming agent is a compound selected from amongacrylic/methacrylic acid ester copolymers, polyvinylpyrrolidones,polyvinyl alcohols, vinyl acetate/vinylpyrrolidone copolymers, vinylacetate/crotonic acid copolymers, methyl vinyl ether/maleic acidcopolymers, polyesters, polyester amides, carboxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, and mixtures thereof.
 8. The preparationof claim 1, wherein the hydrophilic film-forming agent is apolyvinylpyrrolidone.
 9. The preparation of claim 1, wherein theaqueous-alcoholic solution comprises an alcohol selected from amongmethanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol,and a mixture thereof.
 10. The preparation of claim 9, wherein thealcohol is ethanol, n-propanol or isopropanol.
 11. The preparation ofclaim 1, wherein the ratio of alcohol to water is from 9:1 to 1:9. 12.The preparation of claim 11, wherein the ratio of alcohol to watercomprises 2 parts of alcohol to 3 parts of water.
 13. The preparation ofclaim 1, further comprising lactic acid.
 14. The preparation of claim13, wherein the lactic acid is present in an amount from 0.5 percent byweight to 5 percent by weight, relative to the weight of the entirepreparation.
 15. A method for detaching abnormal keritinous materialcomprising applying the preparation of claim 1 to abnormal keritinousmaterial, allowing a sufficient period of time to pass for thepreparation to act on the material, and mechanically detaching thematerial to which the preparation has been applied.
 16. The method ofclaim 15, wherein the abnormal keratinous material is selected fromamong warts, calluses, hard skin, and toenails and fingernails that havebeen changed by fungal attack or psoriatic disease.
 17. A method oftreating or detaching abnormal keratinous material comprising contactingthe abnormal keratinous material with a pharmacuetical preparationcomprising a) one or more nonvolatile constitutents, b) urea in anamount from 30 percent by weight to 90 percent by weight, relative tothe nonvolatile constituents of the preparation, c) a hydrophilicfilm-forming agent, and d) water or an alcohol-water mixture, allowing asufficient period of time to pass for the preparation to act on thematerial, and mechanically detaching the material to which thepreparation has been applied.
 18. The method of claim 17, wherein ureais present in an amount from 35 percent by weight to 85 percent byweight, relative to the nonvolatile constituents or the preparation. 19.The method of claim 17, wherein the hydrophilic film-forming agent ispresent in an amount from 15 percent by weight to 65 percent by weight,relative to the non-volatile constituents of the preparation.
 20. Themethod of claim 17, wherein urea is present in an amount from 39 percentby weight to 83 percent by weight, relative to the nonvolatileconstituents of the preparation.
 21. The method of claim 17, whereinurea is present in an amount from 46 percent by weight to 63 percent byweight, relative to the nonvolatile constituents of the preparation. 22.The method of claim 17, wherein urea is present in an amount from 55percent by weight to 63 percent by weight, relative to the nonvolatileconstituents of the preparation.
 23. The method of claim 17, whereinurea is present in an amount from 25 percent by weight to 35 percent byweight, relative to the nonvolatile constituents of the preparation. 24.The method of claim 17, wherein the hydrophilic film-forming agent ispresent in an amount from 15 percent by weight to 20 percent by weight,relative to the non-volatile constituents of the preparation.
 25. Themethod of claim 17, wherein the abnormal keratinous material is selectedfrom among warts, calluses, hard skin, and toenails and fingernails thathave been changed by fungal attack or psoriatic disease.
 26. The methodof claim 17, wherein the urea is present in an amount from 15 percent.by weight to 35 percent by weight, relative to the weight of the entiresolution.
 27. The method of claim 17, wherein the urea is present in anamount from 25 percent by weight to 33 percent by weight, relative tothe weight of the entire solution.
 28. The method of claim 17, whereinthe hydrophilic film-forming agent is present in an amount fromapproximately 15 percent by weight to approximately 35 percent byweight, realtive to the weight of the entire solution.
 29. The method ofclaim 17, wherein the hydrophilic film-forming agent is present from 17percent to 25 percent, relative to the weight of the entire solution.30. A method of hydrating brittle toenails or fingernails comprisingapplying the preparation of claim 1 to brittle toenails or fingernails.